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Myrbetriq

Pronunciation

Generic Name: Mirabegron
Class: Selective beta-3 Adrenergic Agonists
Chemical Name: 2-Amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]-4-thiazoleacetamide
Molecular Formula: C21H24N4O2S
CAS Number: 223673-61-8

Introduction

Genitourinary smooth muscle relaxant; a selective β3-adrenergic agonist.1 3 4 5 8

Uses for Myrbetriq

Overactive Bladder

Management of overactive bladder for relief of symptoms associated with voiding (e.g., urge urinary incontinence, urgency, frequency).1 10 11 14

May be an appropriate alternative in patients with overactive bladder in whom antimuscarinic agents are ineffective or cannot be tolerated because of adverse anticholinergic effects.3 11 14

Myrbetriq Dosage and Administration

Administration

Oral Administration

Administer orally once daily with water without regard to meals.1

Swallow tablets whole; do not chew, divide, or crush.1

Dosage

Adults

Overactive Bladder
Oral

Initially, 25 mg once daily.1 May increase to 50 mg once daily according to response and tolerance.1

Prescribing Limits

Adults

Overactive Bladder
Oral

Maximum 50 mg daily.1

Special Populations

Hepatic Impairment

Dosage adjustment not necessary in patients with mild hepatic impairment (Child-Pugh class A).1

Maximum 25 mg daily in patients with moderate hepatic impairment (Child-Pugh class B).1 (See Special Populations under Pharmacokinetics.)

Use not recommended in patients with severe hepatic impairment (Child-Pugh class C).1 (See Special Populations under Pharmacokinetics.)

Renal Impairment

Dosage adjustment not necessary in patients with mild or moderate renal impairment (ClCr 30–89 mL/minute).1

Maximum 25 mg daily in patients with severe renal impairment (ClCr 15–29 mL/minute).1 (See Special Populations under Pharmacokinetics.)

Use not recommended in patients with end-stage renal disease (ESRD) (ClCr <15 mL/minute or when hemodialysis required).1 (See Special Populations under Pharmacokinetics.)

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Gender

Dosage adjustment not necessary based on gender.1

Cautions for Myrbetriq

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Cardiovascular Effects

Increased BP reported.1 Worsening of preexisting hypertension reported infrequently.1 Increases in SBP and DBP appeared to be dose related and reversible upon discontinuance of therapy.1

Measure BP periodically, especially in patients with preexisting hypertension.1 Avoid use in patients with severe uncontrolled hypertension (i.e., SBP ≥180 mm Hg, DBP ≥110 mm Hg).1

Causes only minimal QTc interval prolongation and slight increases in HR in healthy individuals.1

Genitourinary Effects

Urinary retention reported in patients with bladder outflow obstruction and in those receiving antimuscarinic agents for treatment of overactive bladder during postmarketing surveillance.1 Use with caution in such patients.1

Interactions with Drugs Metabolized by Hepatic Microsomal Enzymes

Possible increase in systemic exposure to substrates of CYP2D6 when used concomitantly with mirabegron.1 (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.) Appropriate monitoring recommended; dosage adjustment may be necessary, especially in patients receiving CYP2D6 substrates with a narrow therapeutic index.1 (See Specific Drugs under Interactions.)

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats and detected in nursing pups; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Pharmacokinetics not substantially affected by patient age.1 No substantial differences in safety and efficacy relative to younger adults; dosage adjustment not necessary.1

Hepatic Impairment

Increased plasma concentrations of mirabegron reported in patients with moderate hepatic impairment (Child-Pugh class B).1 (See Hepatic Impairment under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Not evaluated in patients with severe hepatic impairment (Child-Pugh class C); use not recommended in such patients.1

Renal Impairment

Increased plasma concentrations of mirabegron reported in patients with severe renal impairment (ClCr 15–29 mL/minute).1 (See Renal Impairment under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Not evaluated in patients with ESRD (ClCr <15 mL/minute or when hemodialysis required); use not recommended in such patients.1

Common Adverse Effects

Hypertension, nasopharyngitis, urinary tract infection, headache.1

Interactions for Myrbetriq

Substrate of CYP isoenzymes 3A4 and 2D6, butyrylcholinesterase, UGT, P-glycoprotein (P-gp), and organic cation transporters (OCT) 1, 2, and 3.1

Moderate, time-dependent inhibitor of CYP2D6 and weak inhibitor of CYP3A.1 Does not induce CYP1A2 or 3A.1 At high concentrations, inhibits P-gp-mediated drug transport.1 Not expected to cause clinically important inhibition of OCT-mediated drug transport.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6: Pharmacokinetic interaction (increased plasma concentrations of CYP2D6 substrates).1 Monitor appropriately and adjust dosage if necessary in patients receiving concomitant therapy with mirabegron and CYP2D6 substrates, especially such drugs with a narrow therapeutic index.1

Substrates of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2E1: Pharmacokinetic interaction unlikely.1 Inhibition of these enzymes not observed at clinically relevant concentrations.1

Specific Drugs

Drug

Interaction

Comments

Antidiabetic agents (e.g., glibenclamide [not commercially available in US], gliclazide [not commercially available in US], tolbutamide)

In vitro metabolism of mirabegron not affected1

Metabolism of glibenclamide or tolbutamide not affected 1

Antimuscarinic agents (e.g., darifenacin, solifenacin)

Potential for additive urinary retention1

Pharmacokinetic interaction unlikely; no substantial effect on pharmacokinetics of mirabegron or solifenacin1

Use concomitantly with caution1

Dosage adjustment of mirabegron or solifenacin not recommended1

Desipramine

Increased peak plasma concentrations and AUC of desipramine1

Use concomitantly with caution; monitor appropriately; dosage adjustment of desipramine may be necessary1

Digoxin

Increased peak plasma concentrations and AUC of digoxin1

Consider initiating digoxin at the lowest recommended dosage; monitor serum digoxin concentrations; titrate dosage carefully to the desired clinical effect1

Flecainide

Possible increased flecainide exposure1

Use concomitantly with caution; monitor appropriately; dosage adjustment of flecainide may be necessary1

Ketoconazole

Increased peak plasma concentrations and AUC of mirabegron1

Dosage adjustment of mirabegron not recommended1

Metformin

Pharmacokinetic interaction unlikely; no substantial effect on pharmacokinetics of mirabegron or metformin1

Dosage adjustment of mirabegron or metformin not recommended1

Metoprolol

Increased peak plasma concentrations and AUC of metoprolol1

Use concomitantly with caution; monitor appropriately; dosage adjustment of metoprolol may be necessary1

Oral contraceptives (e.g., ethinyl estradiol, levonorgestrel)

Pharmacokinetic interaction unlikely; no substantial changes in plasma concentrations of ethinyl estradiol or levonorgestrel1

Dosage adjustment of oral contraceptives not recommended1

Propafenone

Possible increased propafenone exposure1

Use concomitantly with caution; monitor appropriately; dosage adjustment of propafenone may be necessary1

Rifampin

Pharmacokinetic interaction unlikely; no substantial effect on pharmacokinetics of mirabegron1

Dosage adjustment of mirabegron not recommended1

Tamsulosin

Pharmacokinetic interaction unlikely; no substantial effect on pharmacokinetics of mirabegron or tamsulosin1

Dosage adjustment of mirabegron or tamsulosin not recommended1

Thioridazine

Possible increased thioridazine exposure1

Use concomitantly with caution; monitor appropriately; dosage adjustment of thioridazine may be necessary1

Warfarin

Increased mean peak plasma concentrations and AUC of S- and R-warfarin following single dose of warfarin 25 mg with multiple 100-mg doses of mirabegron; however, no effects on INR or PT observed; effects of mirabegron on warfarin pharmacokinetics and pharmacodynamics following multiple doses of warfarin not fully investigated1

Myrbetriq Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability is 29 or 35% following mirabegron dosages of 25 or 50 mg, respectively.1

Peak plasma concentrations achieved at approximately 3.5 hours after oral administration.1 7

Steady-state concentrations achieved within 7 days of once-daily dosing.1 7

Steady-state concentrations following once-daily administration approximately twice as high as that observed following a single dose.1 7

Onset

Symptomatic improvement observed within 4 or 8 weeks with once-daily dosages of mirabegron 50 or 25 mg, respectively.1

Food

Peak plasma concentrations and AUC decreased by 45 and 17%, respectively, following administration of mirabegron 50 mg with a high-fat meal and by 75 and 51%, respectively, following a low-fat meal.1 However, safety and efficacy established when administered without regard to food.1 (See Administration under Dosage and Administration.)

Special Populations

Peak plasma concentrations and AUC were similar following multiple oral doses in geriatric individuals (≥65 years of age) compared with younger adults (18–45 years of age).1 7

Mean peak plasma concentrations and AUC increased by 16 and 17%, respectively, in poor CYP2D6 metabolizers compared with extensive CYP2D6 metabolizers.1

Peak plasma concentrations and AUC increased by approximately 40–50% in females compared with males.1 Systemic exposure about 20–30% higher in females compared with males after adjusting for differences in body weight.1

Pharmacokinetics of mirabegron similar in white and black individuals.1 Increased exposure observed in Japanese individuals compared with North American individuals; extent of differences decreased when peak plasma concentrations and AUC normalized for dose and body weight.1

Mild hepatic impairment (Child-Pugh class A): Mean peak plasma concentrations and AUC increased by 9 and 19%, respectively, compared with those observed in individuals with normal hepatic function.1

Moderate hepatic impairment (Child-Pugh class B): Mean peak plasma concentrations and AUC increased by 175 and 65%, respectively, compared with those observed in individuals with normal hepatic function.1 (See Hepatic Impairment under Dosage and Administration.)

Severe hepatic impairment (Child-Pugh class C): Effect on pharmacokinetics not studied.1 (See Hepatic Impairment under Dosage and Administration.)

Mild renal impairment (estimated GFR 60–89 mL/minute per 1.73 m2): Mean peak plasma concentrations and AUC increased by 6 and 31%, respectively, compared with those observed in individuals with normal renal function.1

Moderate renal impairment (estimated GFR 30–59 mL/minute per 1.73 m2): Mean peak plasma concentrations and AUC increased by 23 and 66%, respectively, compared with those observed in individuals with normal renal function.1 (See Renal Impairment under Dosage and Administration.)

Severe renal impairment (estimated GFR 15–29 mL/minute per 1.73 m2): Mean peak plasma concentrations and AUC increased by 92 and 118%, respectively, compared with those observed in individuals with normal renal function.1 Not studied in patients with ESRD (ClCr <15 mL/minute) or in those requiring hemodialysis.1 (See Renal Impairment under Dosage and Administration.)

Distribution

Extent

Extensively distributed.1

Distributed into erythrocytes; erythrocyte concentrations about twofold higher than plasma concentrations in vitro.1

Distributed into milk in rats and detected in nursing pups.1 Not known whether distributed into human milk.1

Plasma Protein Binding

Approximately 71% (moderate affinity for albumin and α1-acid glycoprotein).1

Elimination

Metabolism

Undergoes hepatic metabolism via multiple pathways involving dealkylation, oxidation, direct glucuronidation, and amide hydrolysis.1 6 CYP isoenzymes 2D6 and 3A4 may be involved in the oxidative metabolism of mirabegron but have limited role in overall drug elimination.1 Butyrylcholinesterase, UGT, and possibly alcohol dehydrogenase also appear to be involved in mirabegron metabolism.1

Two major glucuronide metabolites represent 16 and 11% of total drug exposure, respectively; these metabolites pharmacologically inactive at the β3-adrenergic receptor.1 7

Elimination Route

Eliminated principally by renal clearance via active tubular secretion along with glomerular filtration.1

Approximately 55 and 34% of total radioactivity was recovered in urine and feces, respectively; approximately 25% of the radioactive dose was recovered as unchanged drug excreted in urine and 0% in feces.1

Half-life

Approximately 50 hours.1

Stability

Storage

Oral

Extended-release Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Selective β3-adrenergic agonist.1 3 4 5 8

  • Stimulates human β1-adrenergic receptors at higher than recommended dosages (200 mg).1

  • Relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle resulting in increased bladder capacity via activation of β3-adrenergic receptors.1 5

  • Increased intraocular pressure not observed in healthy individuals following once-daily administration.1

Advice to Patients

  • Importance of reading manufacturer’s patient information before initiating therapy and each time prescription is refilled.1

  • Importance of advising patients to swallow mirabegron tablets whole with water and not to chew, divide, or crush the tablets.1

  • If a dose is missed, omit the dose and take the next dose at the regularly scheduled time; do not take a double dose to make up for the missed dose.1

  • Risk of increased BP.1 Monitor BP periodically, especially in patients with preexisting hypertension.1

  • Risk of urinary retention, especially in patients with bladder outlet obstruction or in those receiving concomitant treatment with antimuscarinic agents.1 Consult a clinician if urinary retention occurs.1

  • Risk of urinary tract infection, tachycardia, rash, or pruritus.1 Consult a clinician if any of these adverse effects occur.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements as well as any concomitant illnesses.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Mirabegron

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, extended-release

25 mg

Myrbetriq

Astellas

50 mg

Myrbetriq

Astellas

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Astellas Pharma US, Inc. Myrbetriq (mirabegron) extended-release tablets prescribing information. Northbrook, IL; 2012 Jun.

3. Gras J. Mirabegron for the treatment of overactive bladder. Drugs Today (Barc). 2012; 48:25-32. [PubMed 22384458]

4. Bhide AA, Digesu GA, Fernando R et al. Use of mirabegron in treating overactive bladder. Int Urogynecol J. 2012; 23:1345-8. Epub 2012 Mar 13. [PubMed 22411211]

5. Tyagi P, Tyagi V, Chancellor M. Mirabegron: a safety review. Expert Opin Drug Saf. 2011; 10:287-94. Epub 2010 Dec 9. [PubMed 21142693]

6. Takusagawa S, van Lier JJ, Suzuki K et al. Absorption, metabolism and excretion of [(14)C]mirabegron (YM178), a potent and selective β(3)-adrenoceptor agonist, after oral administration to healthy male volunteers. Drug Metab Dispos. 2012; 40:815-24. Epub 2012 Jan 23. [PubMed 22269146]

7. Krauwinkel W, van Dijk J, Schaddelee M et al. Pharmacokinetic properties of mirabegron, a beta(3)-adrenoceptor agonist: results from two phase I, randomized, multiple-dose studies in healthy young and elderly men and women. Clin Ther. 2012; 34:2144-60. [PubMed 23063375]

8. Takasu T, Ukai M, Sato S et al. Effect of (R)-2-(2-aminothiazol-4-yl)-4’-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective β3-adrenoreceptor agonist, on bladder function. J Pharmacol Exp Ther. 2007; 321:642-7. [PubMed 17293563]

9. Eltink C, Lee J, Schaddelee M et al. Single dose pharmacokinetics and absolute bioavailability of mirabegron, a β3-adrenoceptor agonist for treatment of overactive bladder. Int J Clin Pharmacol Ther. 2012; 50:838-49. [PubMed 22943933]

10. Khullar V, Amarenco G, Angulo JC et al. Efficacy and tolerability of mirabegron, a β(3)-adrenoceptor agonist, in patients with overactive bladder: results from a randomised European-Australian phase 3 trial. Eur Urol. 2013; 63:283-95. [PubMed 23182126]

11. Nitti VW, Auerbach S, Martin N et al. Results of a Randomized Phase III Trial of Mirabegron in Patients with Overactive Bladder. J Urol. 2013; 189:1388-95. [PubMed 23079373]

12. US Food and Drug Administration. Center for Drug Evaluation and Research. Background document for meeting of Advisory Committee for Reproductive Health Drugs: NDA 202611 mirabegron tablets. 2012 Apr 5. Available from FDA website. Accessed 2013 May 13.

13. Chapple CR, Kaplan SA, Mitcheson D et al. Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and efficacy of mirabegron, a β(3)-adrenoceptor agonist, in overactive bladder. Eur Urol. 2013; 63:296-305. [PubMed 23195283]

14. Otsuki H, Kosaka T, Nakamura K et al. β3-Adrenoceptor agonist mirabegron is effective for overactive bladder that is unresponsive to antimuscarinic treatment or is related to benign prostatic hyperplasia in men. Int Urol Nephrol. 2013; 45:53-60. [PubMed 23212147]

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